Action Points

Note that the study shows that biases related to prostate cancer ascertainment could profoundly affect understanding and recognition of risk factors associated with the disease.

Bias in the decision-making process surrounding prostate biopsy yielded risk factors that had varying associations with actual prostate cancer risk, according to a retrospective analysis of data from the studies.

The data showed a higher likelihood of prostate biopsy in men, ages 60 to 69, men with benign prostatic hyperplasia, and men with a family history of prostate cancer. The odds of prostate biopsy decreased with higher body mass index (BMI), diabetes, or a history of smoking. Medication use, education level, and marital status also influenced a man's odds of prostate biopsy.

Biases related to prostate cancer ascertainment could profoundly affect understanding and recognition of risk factors associated with the disease, reported Catherine Tangen, PhD, of Fred Hutchinson Cancer Research Center in Seattle, and colleagues online in the Journal of Clinical Oncology.

Discussing the potential implications of their findings, the authors wrote, "If all men underwent prostate biopsy, at least 15% would be diagnosed with cancer. As such, if a random risk factor were selected, for example, blue eye color, and it led to an increased risk of biopsy in men with blue eyes, blue eyes would be proven to increase cancer risk."

"The overarching implication of our data is obvious," they added. "Evidence from observational studies suggesting that certain factors reduce/increase the risk of prostate cancer may be seriously flawed because of detection bias. Publication of these observations without careful attention to propensity-to-screen and propensity-to-biopsy bias can have major negative impacts."

Examples of potential negative impacts included selection of an intervention to reduce prostate cancer when the intervention has no effect on cancer risk and wasteful diversion of research resources to laboratory and clinical studies based on flawed observational data.

'Circular Logic'

The author of an accompanying editorial faulted epidemiology researchers' "zeal" to identify risk factors for prostate cancer and "potentially encouraging the wrong patients to undergo screening."

"Men with a family history of prostate cancer are frequently encouraged to undergo PSA testing," wrote Peter Albertsen, MD, of the University of Connecticut in Farmington. "This, in turn, leads to a higher biopsy rate, which, because of the large pool of subclinical disease, leads to higher rates of prostate cancer diagnosis in this group of men, thereby 'confirming' the original hypothesis."

To escape the "circular logic" of selection bias, Albertsen suggested the lessons learned from the long-term follow-up data in the Prostate Testing for Cancer and Treatment trial. The "extraordinary" results showed that prostate cancer screening primarily identified men with low-risk (Gleason 6, 7) disease, which led to a predictably low prostate cancer-specific mortality (1% at 10 years). In contrast, nine times as many men in the trial died of other causes (152/1,643, 9%).

"What can we conclude?" Albertsen asked. "Few screen-detected prostate cancers are lethal. Only a modest number of men benefit from screening and treatment ... Gleason 8, 9, and 10 cancers are usually lethal. Unfortunately, we do not know how to find these cases efficiently or how much radiation or surgery alters the natural course of this disease."

The findings came from an investigation by Tangen and colleagues into the decision-making process surrounding prostate biopsy. Bias in ascertainment could lead to incorporation of spurious risk factors into clinical practice. Their primary objectives were to identify factors associated with an increased likelihood of prostate biopsy, and to explore the impact of biopsy detection bias on commonly reported prostate cancer risk factors.

The analysis involved data from two large trials of prostate cancer prevention: the Prostate Cancer Prevention Trial (PCPT) and the Selenium and Vitamin E Cancer Prevention Trial (SELECT). PCPT involved almost 19,000 men and SELECT involved 35,533 men, all of whom were ages ≥55 with normal digital rectal exam and PSA values at baseline. The authors used data for a subgroup of 8,228 SELECT participants who were assigned to placebo supplements and to a cohort of PCPT participants randomized to placebo (n=8,052) and a subgroup of placebo-treated patients in PCPT who had a study endpoint (n=5,823).

Key Findings

In the SELECT trial, men, ages 60 to 64 (HR 1.29, P<0.001) and 65 to 69 (HR 1.09, P=0.002) were significantly more likely to undergo biopsy than either older or younger men. Black men did not have a higher likelihood of biopsy as compared with white men (HR 1.01), but men with a family history of prostate cancer were more likely (HR 1.52, P<0.001), as those with a history of benign prostate hyperplasia (BPH), which is associated with higher PSA values (HR 1.28, P<0.001).

As compared with men who had a normal-range BMI (<25 kg/m2), those with a BMI of 25 to 29 (overweight) or ≥30 (obese) were 10% to 12% less likely to undergo biopsy (P<0.001). A diabetes diagnosis led to a 34% reduction in the likelihood of biopsy (P<0.001). Additionally, former smokers were 10% less likely and current smokers 37% less likely to undergo biopsy as compared with never smokers (P<0.001). Men who were married or in stable relationships were almost 50% more likely to undergo biopsy (HR 1.48, P<0.001).

Higher education (HR 1.12), aspirin use (HR 1.15), and statin use (HR 1.15) all increased the likelihood that a man would have a biopsy (P<0.001).

Comparison of the SELECT results with outcomes in the two PCPT cohorts showed substantial variation in risk factors associated with prostate biopsy. The odds ratio for biopsy associated with family history varied from 2.20 in the SELECT cohort to 1.50 and 1.41 in the PCPT cohorts; statin use, OR 0.65 in SELECT versus 1.16 and 0.99 in PCPT; aspirin use, OR 0.66 in SELECT versus 1.20 and 1.23 in the PCPT cohorts; black race, OR 1.20 in SELECT versus 1.96 and 1.82 in PCPT.

"Our observations may not be limited to prostate cancer," the authors concluded. "Evidence suggests that other tumors (melanoma, thyroid, and breast) have a significant reservoir of asymptomatic, indolent disease. Because detection testing ... and subsequent biopsy would follow the same pathway, it is likely that conclusions regarding risk factors or preventive strategies for other tumors may suffer from similar confounds."

A study limitation was the lack of generalizability as the results were from men who consented to a prostate cancer prevention trial relative to other cohorts of men.

Tangen disclosed no relevant relationships with industry. One or more co-authors disclosed relevant relationships with Genentech, 3DBiopsy, Genomic Health, Exosome Diagnostics, and Magforce, as well as relevant patent/royalty interests.

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